The actin modulator hMENA regulates GAS6-AXL axis and pro-tumor cancer/stromal cell cooperation.
AXL
GAS6
actin cytoskeleton
cancer-associated fibroblasts
lung cancer
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
05 11 2020
05 11 2020
Historique:
received:
21
01
2020
revised:
04
08
2020
accepted:
10
08
2020
pubmed:
11
9
2020
medline:
28
4
2021
entrez:
10
9
2020
Statut:
ppublish
Résumé
The dynamic interplay between cancer cells and cancer-associated fibroblasts (CAFs) is regulated by multiple signaling pathways, which can lead to cancer progression and therapy resistance. We have previously demonstrated that hMENA, a member of the actin regulatory protein of Ena/VASP family, and its tissue-specific isoforms influence a number of intracellular signaling pathways related to cancer progression. Here, we report a novel function of hMENA/hMENAΔv6 isoforms in tumor-promoting CAFs and in the modulation of pro-tumoral cancer cell/CAF crosstalk via GAS6/AXL axis regulation. LC-MS/MS proteomic analysis reveals that CAFs that overexpress hMENAΔv6 secrete the AXL ligand GAS6, favoring the invasiveness of AXL-expressing pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) cells. Reciprocally, hMENA/hMENAΔv6 regulates AXL expression in tumor cells, thus sustaining GAS6-AXL axis, reported as crucial in EMT, immune evasion, and drug resistance. Clinically, we found that a high hMENA/GAS6/AXL gene expression signature is associated with a poor prognosis in PDAC and NSCLC. We propose that hMENA contributes to cancer progression through paracrine tumor-stroma crosstalk, with far-reaching prognostic and therapeutic implications for NSCLC and PDAC.
Identifiants
pubmed: 32909687
doi: 10.15252/embr.202050078
pmc: PMC7645265
doi:
Substances chimiques
Actins
0
Enah protein, human
0
Microfilament Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e50078Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro (AIRC)
ID : 12182
Organisme : Associazione Italiana per la Ricerca sul Cancro (AIRC)
ID : 19822
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
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